b'2 Important Safety Information LYBALVI (olanzapine and samidorphan) tablets, for oral use For recommendations on starting opioids in LYBALVI-treated patients inBRIEF SUMMARY OF PRESCRIBING INFORMATION non-emergent situations, see DRUG INTERACTIONS section.Cerebrovascular Adverse Reactions in Elderly Patients withLeukopenia, Neutropenia, and Agranulocytosis (including fatal(For complete details, see full Prescribing Information) Risk of Resuming Opioids in Patients with Prior Opioid UseDementia-Related Psychosis, including stroke, transient ischemiacases): Perform complete blood counts in patients with a history ofPatients with a history of chronic opioid use prior to treatment with LYBALVI may attack, and fatalities. See Boxed Warning. a clinically significant low white blood cell (WBC) count or history ofWARNING: INCREASED MORTALITY IN ELDERLY PATIENTS WITH have decreased opioid tolerance if LYBALVI therapy is interrupted or discontinued. Precipitation of Severe Opioid Withdrawal in Patients who areleukopenia or neutropenia. Discontinue LYBALVI if clinically significantDEMENTIA-RELATED PSYCHOSISAdvise patients that this decreased tolerance may increase the risk of opioid Physiologically Dependent on Opioids: LYBALVI can precipitatedecline in WBC occurs in the absence of other causative factors. Elderly patients with dementia-related psychosis treated withoverdose if opioids are resumed at the previously tolerated dosage.opioid withdrawal in patients who are dependent on opioids, whichDysphagia: Use LYBALVI with caution in patients at risk for aspiration. antipsychotic drugs are at an increased risk of death. LYBALVI is notNeuroleptic Malignant Syndrome: Neuroleptic Malignant Syndrome (NMS), can lead to an opioid withdrawal syndrome, sometimes requiringSeizures: Use LYBALVI with caution in patients with a history ofapproved for the treatment of patients with dementia-related psychosis.a potentially fatal symptom complex, has been reported in association with hospitalization. LYBALVI is contraindicated in patients who are usingseizures or with conditions that lower the seizure threshold. administration of antipsychotic drugs. Clinical manifestations of NMS are opioids or undergoing acute opioid withdrawal. Prior to initiatingINDICATIONS AND USAGE hyperpyrexia, muscle rigidity, delirium, and autonomic instability. Additional signs LYBALVI, there should be at least a 7-day opioid-free interval from lastPotential for Cognitive and Motor Impairment: Because LYBALVILYBALVI is indicated for the treatment of:may include elevated creatine phosphokinase, myoglobinuria (rhabdomyolysis), and use of short-acting opioids, and at least a 14-day opioid-free intervalmay cause somnolence, impair judgment, thinking, or motor skills, Schizophrenia in adults acute renal failure.from the last use of long-acting opioids. Explain the risks associatedcaution patients about operating hazardous machinery, including with precipitated withdrawal and the importance of giving an accuratemotor vehicles, until they are certain that LYBALVI does not affect Bipolar I disorder in adults If NMS is suspected, immediately discontinue LYBALVI and provide intensive account of last opioid use to patients and caregivers. them adversely. | symptomatic treatment and monitoring.Acute treatment of manic or mixed episodes as monotherapy and as Vulnerability to Life-Threatening Opioid Overdose: Attempting toBody Temperature Dysregulation: Use LYBALVI with caution inadjunct to lithium or valproateDrug Reaction with Eosinophilia and Systemic Symptoms: Drug Reaction overcome opioid blockade with high or repeated doses of exogenouspatients who may experience conditions that increase core body| Maintenance monotherapy treatmentwith Eosinophilia and Systemic Symptoms (DRESS) has been reported withopioids could lead to life-threatening or fatal opioid intoxication,temperature (e.g., strenuous exercise, extreme heat, dehydration, orCONTRAINDICATIONS exposure to olanzapine, a component of LYBALVI. DRESS may present with a particularly if LYBALVI therapy is interrupted or discontinuedconcomitant use with anticholinergics). cutaneous reaction (such as rash or exfoliative dermatitis), eosinophilia, fever, subjecting the patient to high levels of unopposed opioid agonist asLYBALVI is contraindicated in patients:and/or lymphadenopathy with systemic complications such as hepatitis, nephritis, the samidorphan blockade wanes. Inform patients of the potentialAnticholinergic (Antimuscarinic) Effects: Olanzapine, a component who are using opioidspneumonitis, myocarditis, and/or pericarditis. DRESS is sometimes fatal. consequences of trying to overcome the opioid blockade and theof LYBALVI, was associated with constipation, dry mouth, and who are undergoing acute opioid withdrawalDiscontinue LYBALVI if DRESS is suspected.serious risks of taking opioids concurrently with LYBALVI or whiletachycardia. Use LYBALVI with caution with other anticholinergicIf LYBALVI is administered with lithium or valproate, refer to the lithium or valproateMetabolic Changes: Atypical antipsychotic drugs, including LYBALVI, have been transitioning off LYBALVI. In emergency situations, if a LYBALVI- medications and in patients with urinary retention, prostaticPrescribing Information for the contraindications for these products. associated with metabolic changes that include hyperglycemia, diabetes mellitus, treated patient requires opioid treatment as part of anesthesia orhypertrophy, constipation, paralytic ileus or related conditions. Indyslipidemia, and body weight gain. While all drugs in the class have been shown to analgesia, discontinue LYBALVI. Opioids should be administered bypostmarketing experience, the risk for severe adverse reactionsWARNINGS AND PRECAUTIONS produce some metabolic changes, each drug has its own specific risk profile.properly trained individual(s) and patient should be continuously(including fatalities) was increased with concomitant use ofIncreased Mortality in Elderly Patients with Dementia-Related Psychosis: Hyperglycemia, in some cases extreme and associated with ketoacidosis or monitored in a setting equipped and staffed for cardiopulmonaryanticholinergic medications. Elderly patients with dementia-related psychosis treated with antipsychotic drugshyperosmolar coma or death, has been reported in patients treated with atypical resuscitation. Patients with a history of chronic opioid use priorHyperprolactinemia: LYBALVI elevates prolactin levels. Galactorrhea,are at an increased risk of death. In placebo-controlled clinical trials of elderlyantipsychotics. Any patient treated with LYBALVI should be monitored for symptoms to treatment with LYBALVI may have decreased opioid tolerance ifamenorrhea, gynecomastia, and impotence have been reported inpatients with dementia-related psychosis, the incidence of death in olanzapine- of hyperglycemia including polydipsia, polyuria, polyphagia, and weakness. Patients LYBALVI therapy is interrupted or discontinued. Advise patients thatpatients receiving prolactin-elevating compounds. treated patients was significantly greater than in placebo-treated patients (3.5%who develop symptoms of hyperglycemia during treatment with LYBALVI should vs 1.5%, respectively). Analyses of 17 placebo-controlled trials (modal duration of this decreased tolerance may increase the risk of opioid overdose ifRisks Associated with Combination Treatment with Lithium or10 weeks), largely in patients taking atypical antipsychotic drugs, revealed a risk ofundergo fasting blood glucose testing. In some cases, hyperglycemia has resolved opioids are resumed at the previously tolerated dosage. Valproate: If LYBALVI is administered with lithium or valproate, referdeath in the drug-treated patients of between 1.6 to 1.7 times that seen in placebo- when the atypical antipsychotic was discontinued; however, some patients required Neuroleptic Malignant Syndrome, a potentially fatal reaction.to the lithium or valproate Prescribing Information for a description oftreated patients. Over the course of a typical 10-week controlled trial, the rate ofanti-diabetic treatment despite discontinuation of the suspect drug. Patients Signs and symptoms include hyperpyrexia, muscle rigidity,the risks for these products. death in drug-treated patients was about 4.5%, compared to a rate of about 2.6%starting treatment with LYBALVI should undergo fasting blood glucose testing at the delirium, autonomic instability, elevated creatinine phosphokinase,Most common adverse reactions observed in clinical trials were: in the placebo group. Although the causes of death were varied, most of the deathsbeginning of treatment and periodically during treatment.myoglobinuria (and/or rhabdomyolysis), and acute renal failure.Schizophrenia (LYBALVI): weight increased, somnolence, dry mouth,appeared to be either cardiovascular (e.g., heart failure, sudden death) or infectiousAntipsychotics have caused adverse alterations in lipids. Patients starting treatment Manage with immediate discontinuation, intensive symptomaticand headache (e.g., pneumonia) in nature. LYBALVI is not approved for the treatment of patientswith LYBALVI should undergo fasting lipid profile testing at the beginning of treatment, and close monitoring. with dementia-related psychosis. treatment and periodically during treatment.Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS),Bipolar I Disorder, Manic or Mixed Episodes (olanzapine): asthenia, Cerebrovascular Adverse Reactions, Including Stroke in Elderly Patients withWeight gain has been observed with use of antipsychotics. Monitor weight prior to a potentially fatal condition reported with exposure to olanzapine,dry mouth, constipation, increased appetite, somnolence, Dementia-Related Psychosis: Cerebrovascular adverse reactions (e.g., stroke,initiating LYBALVI and frequently thereafter.a component of LYBALVI. Symptoms include a cutaneous reactiondizziness, tremor transient ischemic attack), including fatalities, were reported in patients in trialsTardive Dyskinesia: Tardive dyskinesia, a syndrome consisting of potentially (such as rash or exfoliative dermatitis), eosinophilia, fever, and/or Bipolar I Disorder, Manic or Mixed Episodes, adjunct to Lithium orof olanzapine in elderly patients with dementia-related psychosis. In placebo- irreversible, involuntary, dyskinetic movements, may develop in patients treated lymphadenopathy with systemic complications such as hepatitis,Valproate (olanzapine): dry mouth, dyspepsia, weight gain, increasedcontrolled trials, there was a significantly higher incidence of cerebrovascularwith antipsychotic drugs. The risk appears to be highest among the elderly, nephritis, pneumonitis, myocarditis, and/or pericarditis. Discontinueappetite, dizziness, back pain, constipation, speech disorder,adverse reactions in patients treated with olanzapine compared to patients treatedespecially elderly women, but it is not possible to predict which patients are likely to if DRESS is suspected. increased salivation, amnesia, paresthesia with placebo. LYBALVI is not approved for the treatment of patients with dementia- develop the syndrome. Whether antipsychotic drug products differ in their potential Metabolic Changes, including hyperglycemia, diabetes mellitus,Concomitant Medication: LYBALVI is contraindicated in patientsrelated psychosis. to cause tardive dyskinesia is unknown. dyslipidemia, and weight gain. Hyperglycemia, in some cases extremewho are using opioids or undergoing acute opioid withdrawal.Precipitation of Severe Opioid Withdrawal in Patients Who AreThe risk of developing tardive dyskinesia and the likelihood that it will become and associated with ketoacidosis or hyperosmolar coma or death,Concomitant use of LYBALVI is not recommended with strong CYP3A4Physiologically Dependent on Opioids: Samidorphan, an opioid antagonist thatirreversible increases with the duration of treatment and the cumulative dose. The has been reported in patients treated with atypical antipsychotics.inducers, levodopa and dopamine agonists. Reduce dosage ofis a component of LYBALVI, can precipitate opioid withdrawal in patients whosyndrome can develop after a relatively brief treatment period, even at low doses. It Any patient treated with LYBALVI should be monitored for symptomsLYBALVI when using with strong CYP1A2 inhibitors. Increase dosageare dependent on opioids, which can lead to an opioid withdrawal syndrome,may also occur after discontinuation of treatment. of hyperglycemia including polydipsia, polyuria, polyphagia, andof LYBALVI with CYP1A2 inducers. Use caution with diazepam, alcohol,sometimes requiring hospitalization. Therefore, LYBALVI is contraindicated inTardive dyskinesia may remit, partially or completely, if antipsychotic treatment weakness. In some cases, hyperglycemia has resolved when theother CNS acting drugs, or in patients receiving anticholinergicpatients who are using opioids or undergoing acute opioid withdrawal. Prior tois discontinued. Antipsychotic treatment itself, however, may suppress (or atypical antipsychotic was discontinued; however, some patients(antimuscarinic) medications. Monitor blood pressure and reduceinitiating LYBALVI, there should be at least a 7-day opioid-free interval from last usepartially suppress) the signs and symptoms of the syndrome, possibly masking required anti-diabetic treatment despite discontinuation of thedosage of antihypertensive drug in accordance with its approvedof short-acting opioids, and at least a 14-day opioid-free interval from the last usethe underlying process. The effect of symptomatic suppression on the long-term suspect drug. Measure weight and assess fasting glucose and lipidsproduct labeling. of long-acting opioids. Explain the risks associated with precipitated withdrawalcourse of the syndrome is unknown. when initiating LYBALVI and monitor periodically. Pregnancy: May cause extrapyramidal and/or withdrawal symptomsand the importance of giving an accurate account of last opioid use to patientsin neonates with third trimester exposure. Advise patients to notifyand caregivers. Given these considerations, LYBALVI should be prescribed in a manner that is most Tardive Dyskinesia (TD): Risk of developing TD (a syndrome oftheir healthcare provider if they become pregnant or intend toVulnerability to Life-Threatening Opioid Overdose likely to reduce the risk of tardive dyskinesia. Chronic antipsychotic treatment potentially irreversible, involuntary, dyskinetic movements) and thebecome pregnant during treatment with LYBALVI. Inform patientsRisk of Opioid Overdose from Attempts to Overcome Samidorphan Blockade:should generally be reserved for patients: 1) who suffer from a chronic illness that likelihood it will become irreversible increases with the durationthat there is a pregnancy exposure registry that monitors pregnancyLYBALVI contains samidorphan, an opioid antagonist. Attempting to overcomeis known to respond to antipsychotic drugs; and 2) for whom alternative, effective, of treatment and the cumulative dose. The syndrome can developoutcomes in women exposed to LYBALVI during pregnancy. LYBALVIs opioid blockade with high or repeated doses of exogenous opioids (e.g.,but potentially less harmful treatments are not available or appropriate. In patients after a relatively brief treatment period, even at low doses, or afterbecause of ineffective analgesia or opioid withdrawal symptoms) could lead to life- who do require chronic treatment, use the lowest dose and the shortest duration of discontinuation. Given these considerations, LYBALVI should beRenal Impairment: LYBALVI is not recommended for patients withtreatment producing a satisfactory clinical response should be sought. Periodically prescribed in a manner that is most likely to reduce the risk of tardiveend-stage renal disease (eGFR of 15 mL/minute/1.73 m 2 ). threatening or fatal opioid intoxication (e.g., respiratory arrest, circulatory collapse),reassess the need for continued treatment. dyskinesia. If signs and symptoms of TD appear, drug discontinuationparticularly if LYBALVI therapy is interrupted or discontinued, subjecting the patient should be considered. To report SUSPECTED ADVERSE REACTIONS, contact Alkermesto high levels of unopposed opioid agonist as the samidorphan blockade wanes.If signs and symptoms of tardive dyskinesia appear in a patient on LYBALVI, at 1-888-235-8008 or FDA at 1-800-FDA-1088 or www.fda.gov/ Inform patients of the potential consequences of trying to overcome the opioiddrug discontinuation should be considered. However, some patients may require Orthostatic Hypotension and Syncope: Monitor orthostatic medwatch. blockade and the serious risks of taking opioids concurrently with LYBALVI or whiletreatment with LYBALVI despite the presence of the syndrome.vital signs in patients who are vulnerable to hypotension, transitioning off LYBALVI.Orthostatic Hypotension and Syncope: Atypical antipsychotics cause orthostatic patients with known cardiovascular disease, and patients with Please see the Brief Summary of full Prescribing Information,In emergency situations, if a LYBALVI-treated patient requires opioid treatment ashypotension and syncope. Generally, the risk is greatest during initial dosecerebrovascular disease. including Boxed Warning, for LYBALVI on the following pages. part of anesthesia or analgesia:titration and when increasing the dose. In the 4-week, placebo-controlled study,Falls: LYBALVI may cause somnolence, postural hypotension,Reference: LYBALVI [prescribing information]. Waltham, MA: Discontinue LYBALVI,from analysis of the vital signs data, rates of orthostatic hypotension were lessand motor and sensory instability, which may lead to falls, andthan 2% in LYBALVI- and placebo-, and olanzapine-treated patients. In theconsequently, fractures or other injuries. Assess patients for riskAlkermes, Inc.; 2021. Opioids should be administered by individual(s) trained in the use of anesthetic24-week, olanzapine-controlled study, from analysis of the vital signs data, rateswhen using LYBALVI. drugs and the management of the respiratory effects of opioids, specifically theof orthostatic hypotension in LYBALVI-treated patients were 3.7%, compared to establishment and maintenance of a patent airway and assisted ventilation, and 0.4% in olanzapine-treated patients.ALKERMES is a registered trademark of Alkermes, Inc. LYBALVI is a registered trademark and the LYBALVI logo is a trademark ofAppropriately trained personnel should continuously monitor the patient in a Alkermes Pharma Ireland Limited, both used by Alkermes, Inc., under license. 2022 Alkermes, Inc. All rights reserved. LYB-001276setting equipped and staffed for cardiopulmonary resuscitation.'